Deuterated benzopyran compounds and application thereof

ABSTRACT

The present invention discloses deuterated benzopyran compounds having structure features as shown in Formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, or prodrug molecules thereof. With excellent anti-inflammatory and analgesic effects and the capability to inhibit growth of tumor cells, such compounds are novel COX-2 selective inhibitors. The compounds and pharmaceutically acceptable salts thereof disclosed by the present application can be applied in preparing anti-inflammatory and analgesic drugs and drugs for treating or preventing tumors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.14/401,600, filed Nov. 17, 2014, which is a U.S. National PhaseApplication of PCT Application No. PCT/CN2012/079968, filed on Aug. 10,2012, which claims benefit of CN 201210202059.X filed Jun. 18, 2012. Theentire disclosures of the applications identified in this paragraph areincorporated herein by references.

TECHNICAL FIELD

The present invention belongs to the field of chemical pharmaceuticals,particularly relates to deuterated benzopyran compounds and applicationthereof.

BACKGROUND OF THE PRESENT INVENTION

Inflammation, as one of extremely common diseases, severely threatenshuman health and even brings great impacts on people's living quality.Taking arthritis which is one of the most common chronic diseases asexample, it is estimated that there are a total of more than one hundredtypes, of which osteoarthritis and rheumatoid arthritis are the mostcommon. There are about 355 million people suffering from a variety ofjoint diseases around the world, of which about 190 million people areosteoarthritis patients and more than 16.5 million people are rheumatoidarthritis patients. It is estimated that there are more than 100 millionarthritis patients in China and this number is increasing every year.Although there are already anti-inflammatory and analgesic drugs(belonging to COX-2 inhibitors) available on the market, it is stillunable to meet the increasing needs of clinical patients. Accordingly,the research and development of anti-inflammatory and analgesic drugs isstill an important direction of drug development.

The traditional nonsteroidal anti-inflammatory drugs (traditional NSAIDsor non-selective NSAIDs) serve as the main anti-inflammatory andanalgesic drugs for treating arthritis, including Ibuprofen, Diclofenacsodium, Meloxicam, Nabumetone, Naproxen, etc. Such drugs, on one hand,have anti-inflammatory and analgesic effects, and on the other hand,lead to a variety of severe gastrointestinal adverse reactionscomplications, for example, epigastric distress, ulcer, gastrointestinalbleeding, perforation and intestinal obstruction and etc. An estimated60%-80% of such severe gastrointestinal complications have no signal ofoutbreak. It is speculated by some scholars that, possibly becausemasking the progress of ulcer by the analgesic effects of such drugscauses the chronic blood loss unconsciously, resulting in aggravationeven massive hemorrhage without warning, making it too difficult toprevent or control. It is an unfortunate fact that, in America, about16,500 people, as high as the number of those died of AIDS, died ofgastrointestinal bleeding caused by such traditional nonsteroidalanti-inflammatory drugs in 1997, increasing the medical burden onsociety and family. Therefore, while remaining the excellentanti-inflammation and analgesic effects, developing anti-inflammatoryand analgesic drugs capable of decreasing the incidences of severeadverse reactions becomes one of the issues concerned by the medicalprofession around the world.

The history of nonsteroidal anti-inflammatory drugs (NSAIDs) is astruggle against pain. Specifically, in 1899, the Bayer Company inGermany marketed a variant, acetylsalicylic acid, under the name ofaspirin which is the prototype of NSAIDs. Aspirin marked the beginningof the modern anti-inflammatory treatment era, and over the nexthalf-century, served as the main drug for anti-inflammatory treatment.Thereafter, NSAIDs of many types and structures had been successfullydeveloped and marketed. Pyrazolone drugs, appeared in the 1950s, haveexcellent anti-inflammatory and analgesic effects, but deleteriouseffects on the bone marrow and other systems. One of indole acetic aciddrugs (Indometacin), appeared in the 1960s, had been replaced bySulindac and Acemetacin marketed in 1980s, due to its severe adversereactions on gastrointestinal tract, liver and kidney and thusinapplicability to the old and patients suffering from liver, kidney andcardiovascular complications, in spite of excellent anti-inflammatory,analgesic and antipyretic effects. In 1970s, propionic acid drugs forexample Ibuprofen, phenylacetic acid drugs for example DiclofenacSodium, Oxicams for example Proxicam, Anthranilic acid drugs for exampleEtofenamate appeared. In 1980s, Naproxen was also one of the productsmarketed. In 1990s, cyclooxygenase-2 (COX-2) selective inhibitors weredeveloped. NSAIDs, which can selectively inhibit the COX-1 and COX-2enzyme activity, become the mainstream of research and development ofanti-inflammatory and analgesic drugs.

Cyclooxygenases (COXs) are primary targets of the nonsteroidalanti-inflammatory drugs (NSAIDs). COXs function as catalyticsynthesizing the intermediates, i.e., endoperoxides. (PGG2 and PGH2), ofbioactive media such as prostaglandins (PGs) and thromboxane A2 (TXA2).In recent years, it has been found that COXs have two isomers, i.e.,COX-1 and COX-2. These two isomers are 60% homologous, but different inboth cellular distribution of tissues and biologic functions. PGE2 andPGI2 catalytically synthesized by COX-1 existing in normal tissues havecellular stabilization and protection functions. For example, in thegastric mucosa, PGE2 may promote the secretion of gastric mucus andprotect the gastric mucosa. Gastric mucosa damage will be caused in thecase of inhibited PGE2 biosynthesis or hyposecretion. COX-2 iscytokine-induced and just exists in the damaged tissues. Prostaglandinscatalytically synthesized by COX-2 are inflammatory with high capabilityof Inducing inflammation and pain. The selective inhibition of COX-2reduces the prostaglandins synthesized, so that the anti-inflammatoryand analgesic effects are realized. As can be seen, the selectiveinhibition of COX-2 achieves not only the anti-inflammatory andanalgesic purposes and also the reduced toxic or side effects to thegastrointestinal tract and kidney. Therefore, seeking COX-2 selectiveinhibitors is a major direction for the research and development of anew generation of NSAIDs. The fundamental research of COX-2 and theclinical application and safety assessment of COX-2 selective inhibitorsbecome the common concerns of many subjects.

Cyclooxygenase (COX) protein was once believed to be produced by asingle gene. COX is fundamentally composed of three independently foldedunits, i.e., epidermal growth factor domain, membrane binding domain andenzymatic activity domain. In 1990, the second isoenzyme of COX, whichis different from the “typical” COX in both structure and function, wasfound in various cells. Hence, the typical COX as constitutive enzymewas named as COX-1 and the other COX as inducible enzyme was named asCOX-2. The protein of COX-2 is made up of 604 amino acids. According tothe well known crystal structure of COX, by the sequencing of COX-2, thedifference in active sites between COX-2 and COX-1 is determined. The523rd amino acid of COX-2 is valine, the structure of which is smallerthan the leucine in a corresponding site of COX-1. Another differencelies in that there is a small recess which is produced in a differentposition on the 384th side-chain of leucine between COX-1 and COX-2.This difference exists because there are large non-steroidalanti-inflammatory drugs (NSAIDS) binding sites, so that the inhibitiondedicated to COX-2 from the substrate is realized by enhancing theaffinity with respect to the occupation of the macromolecule substrate.The discovery of COX-2 provides important theoretic basis for thedevelopment and use of the COX-2 selective inhibitors.

Most scholars believe that the pharmacological effects and adversereactions of NSAIDs depend on the level of inhibition to COX-1 andCOX-2. Specifically, the level of inhibition to COX-1 is higher, theadverse reactions on the digestive tract, kidney and etc. are severer;and, the level of inhibition to COX-2 is higher, the anti-inflammatoryand analgesic effects are greater. Coxibs NSAIDs (COX-2 selectiveinhibitors) represented by Celecoxib, Rofecoxib and Valdecoxib areemerged in this context, with less adverse reactions on thegastrointestinal tract as their major advantage. It is generallyrecognized that COX-2 selective inhibitors have less adverse reactionson the gastrointestinal tract and less toxicity to the kidney thancommon non-steroidal anti-inflammatory drugs as they do not work onCOX-1 and have no impact on the synthesis of PGI2 which may protect thegastrointestinal tract and the kidney. The COX-2 selective inhibitors,for example, Celecoxib, have an efficacy on chronic inflammationapproximating to NSAIDs. However, they have quick analgesic effectsslightly weaker when compared with ibuprofen and will cause a highincidence of cardiovascular side-effects. Over time, more adversereactions have been further recognized, including: the recognition ofadverse cardiovascular events caused as the COX-2 selective inhibitorshave no inhibition to COX-1 and thromboxane A2 (TXA2) on the platelets.

A consensus has been reached on the clinical research of the COX-2inhibitors. Specifically, due to different chemical structures, drugseven of the type may be completely different in safety; and some COX-2inhibitors may even have cardiovascular protection function. The mostimportant is that COX-2 selective inhibitors can produce more benefitsthan the traditional non-steroidal anti-inflammatory drugs, particularlyin the reduction of gastrointestinal side effects. Hence, the search anddevelopment of anti-inflammatory and analgesic drugs still focus onCOX-2 selective inhibitors.

Benzopyran compounds themselves, as novel COX-2 selective inhibitors,have carboxyl groups which will not be reacted with the hydrophobicgroups in the active sites of COX-2. Benzopyran drug candidates,differentiated from diarylheterocyclicoxib compounds, have the sameefficacy and selectivity as the diarylheterocyclicoxib compounds andshow the capability to reduce the tactile allodynia in the rat model ofneuropathic pain. It has been proved that benzopyran compounds havebetter treatment effects on inflammation and pain than the existingcoxib compounds, and such compounds have a potential kidney protectionfunction, thereby reducing the possibility of hypertension caused by theinternal structure and the pharmacological and physiological properties.Hence, the development of such COX-2 selective inhibitors asanti-inflammatory and analgesic drugs is of great significance.

SUMMARY OF THE PRESENT INVENTION

Accordingly, an objective of the present invention is to provide noveldeuterated benzopyran compounds.

The technical solution will be described specifically as below.

Deuterated benzopyran compounds having structure features as shown inFormula (I), or pharmaceutically acceptable salts or stereoisomersthereof, or prodrug molecules thereof:

X is optionally selected from O, S or NR^(a);

R^(a) is optionally selected from:

1) H;

2) C₁-C₃ alkyl;

3) C₃-C₆ Cycloalkyl;

4) C₁-C₃ alkyl substituted by one or two halogen; and

5) aryl.

R is optionally selected from:

1) carboxyl;

2) acylamino;

3) alkysulfonyl; and

4) alkoxycarbonyl;

R₁ is optionally selected from:

1) haloalkyl;

2) alkyl;

3) aralkyl; and

4) cycloalkyl;

R₂ is selected from one or more of the following groups to formdeutero-naphthyl:

1) deuterium;

2) halogen;

3) alkyl or deutero-alkyl;

4) aralkyl or deutero-aralkyl;

5) alkoxy or deutero-alkoxy;

6) aryloxy or deutero-aryloxy;

7) heteroaryloxy or deutero-heteroaryloxy;

8) arylalkoxy or deutero-arylalkoxy;

9) heteroarylalkoxy or deutero-heteroarylalkoxy;

10) haloalkoxy or deutero-haloalkoxy;

11) haloalkoxy or deutero-haloalkoxy;

12) amino or deutero-amino;

13) substituted amino or substituted deutero-amino;

14) sulfamidyl or deutero-sulfamidyl;

15) substituted sulfamidyl or substituted deutero-sulfamidyl;

16) carbonyl;

17) substituted carbonyl or substituted deutero-carbonyl; and

R₂ reacts with benzene to form deutero-naphthyl.

In some of embodiments, X is O or S;

R is selected from carboxyl, C₁-C₃ Cyclocarbonyl, aryl-substituted C₁-C₃Cyclocarbonyl and C₁-C₃ alkoxycarbonyl; and

R₁ is selected from haloalkyl, cycloalkyl and phenyl.

R₂ is selected from one or more of the following groups to formdeuterated compounds:

1) deuterium;

2) halogen;

3) alkyl or deutero-alkyl;

4) alkoxy or deutero-alkoxy;

5) haloalkyl or deutero-haloalkyl;

6) alkylamino or deutero-alkylamino;

7) nitryl;

8) alkylated sulfamidyl or deutero-alkylated sulfamidyl;

10) acyl or deutero-acyl;

11)aryl or deutero-aryl; and

R2 reacts with benzene to form deutero-naphthyl.

In some of embodiments, X is O or S; R is carboxyl; R₁ is rifluoromethylor pentafluoromethyl;

R2 is optionally selected from one or more groups to form deuteratedcompounds:

1) deuterium;

2) halogen;

3) methyl, ethyl, isopropyl, tert-butyl, or, deutero-methyl,deutero-ethyl, deutero-isopropyl, deutero-tert-butyl;

4) trifluoromethyl, trifluoromethoxy;

5) haloalkyl or deutero-haloalkyl;

6) alkylated sulfamidyl or deutero-alkylated sulfamidyl;

7) methylsulfonyl or deutero-methylsulfonyl;

8) aroyl or deutero-aroyl;

9) aryl or deutero-aryl; and

R2 reacts with benzene to form deutero-naphthyl.

In some of embodiments, the X is O; R is carboxyl; R₁ trifluoromethyl;

R2 is optionally selected from one or more groups to form deuteratedcompounds:

1) deuterium;

2) halogen;

3) methyl, ethyl, isopropyl, tertbutyl, or, deutero-methyl,deutero-ethyl, deutero-isopropyl, deutero-tert-butyl;

4) trifluoromethyl, trifluoromethoxy;

5) haloalkyl or deutero-haloalkyl; and

6) aryl or deutero-aryl.

In some of embodiments, the compound is selected from:

-   6-(methyl-D3)-2-(trifluoromethyl)-2H-chromence-3-carboxylic acid;-   ethyl    8-(ethyl-D5)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   6-chloro-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   6-bromo-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   6-chloro-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   6-bromo-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   8-chloro-6-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   6,8-dibromo-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   7-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid;-   7-(ethyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid;-   6-chloro-7-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   8-(1-methylhexyl-D15)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   6-chloro-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   6-chloro-7-(1,1-dimethylhexyl-D17)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   6-chloro-8-(1-methylhexyl-D15)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   7-(1-methylhexyl-D15)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   6-chloro-7-(hexyl-D13)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid;-   8-(hexyl-D13)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid;-   7,8-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid;    and-   6-chloro-8-(hexyl-D13)-2-(trifluoromethyl)-2H-chromene-3-carboxylic    acid.

Another objective of the present invention is to provide an applicationof the deuterated benzopyran compounds described above, orpharmaceutically acceptable salts or stereoisomers thereof, or prodrugmolecules thereof, in preparing anti-inflammatory and analgesic drugs orpreparing drugs for preventing or treating tumors.

The technical solution will be described specifically as below.

Disclosed is an application of the deuterated benzopyran compoundsdescribed above, or pharmaceutically acceptable salts or stereoisomersthereof, or prodrug molecules thereof, in preparing anti-inflammatoryand analgesic drugs or preparing drugs for preventing or treatingtumors.

In some of embodiments, the inflammation mainly comprises rheumatoidarthritis, gouty arthritis, osteoarthritis and rachitis, furthercomprises one of systemic lupus erythematosus, psoriasis, eczema, skininflammation and postpartum inflammation, bowel disease, gastritis,irritable bowel syndrome, headache, exarteritis, thyroiditis, aplasticanemia, retinitis, conjunctivitis, retinopathy, uveitis, hemeralopia,acute ocular tissue injury, viral infection and cystic fibrosis,allergic rhinitis, postpartum pain, toothache, muscle pain, cancer pain,aneurysm, coronary plaque inflammation, inflammation caused by bacteria,inflammation caused by viruses, inflammation caused by surgery, ocularvascular hyperplasia, retinal vascular hyperplasia and gastriculcer.

In some of embodiments, the tumor is one of hemangioma, endometriosis,gastrointestinal stromal tumor, histiocytic lymphoma, non-small celllung cancer, small-cell lung cancer, lung adenocarcinoma, squamous cellcarcinoma, pancreatic cancer, breast cancer, prostate cancer, livercancer, skin cancer, squamous cell carcinoma, nasopharyngeal carcinomaand leukemia.

Another objective of the present invention is to provide pharmaceuticalcompositions.

The technical solution will be described specifically as below.

Disclosed are pharmaceutical compositions composed of the deuteratedbenzopyran compounds described above, or pharmaceutically acceptablesalts or stereoisomers thereof, or prodrug molecules thereof, andpharmaceutically acceptable carriers.

When any variable (e.g., R1, R, etc.) occurs more than one time in anyconstituent, its definition on each occurrence is independent at everyother occurrence. Also, combinations of substituents and variables arepermissible only if such combinations result in stable compounds. Linesdrawn into the ring systems from substituents indicate that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.

The term “deuterium” as used herein is intended to mean a singledeuterium atom, where the deuterium radicals are attached onto thecarbon atoms or oxygen atoms to form deuterted compounds. As usedherein, the terms “alkyl” and “alkylene” are intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁-C₅” as in“C₁-C₅ alkyl” is defined to include groups having 1, 2, 3, 4 or 5 carbonatoms in a linear or branched arrangement. For example, “C₁-C₅ alkyl”specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, pentyl, etc. The term “cycloalkyl” means a monocyclicsaturated aliphatic hydrocarbon group having the specified number ofcarbon atoms. For example, “cycloalkyl” includes cyclopropyl,methyl-cyclopropyl, 2,2-dimethylcyclobutyl, 2-ethyl-cyclopentyl,cyclohexyl, etc.

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

The term “aryl” as used herein is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 atoms in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydronaphthyl, indanyl and biphenyl. In cases where thearyl substituent is bicyclic and one ring is non-aromatic, it isunderstood that attachment is via the aromatic ring.

The term “heteroaryl” as used herein represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furyl,thienyl, benzothiophenyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl,isoxazoyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrrolyl and tetrahydroquinoline. As with the definition of heterocyclebelow, “heteroaryl” is also understood to include the N-oxide derivativeof any nitrogen-containing heteroaryl. In cases where the heteroarylsubstituent is bicyclic and one ring is non-aromatic or contains noheteroatoms, it is understood that attachment is via the aromatic ringor via the heteroatom containing ring, respectively.

Sulfamine as used herein is “—SO2NH2-”. As appreciated by those skilledin the art, “halo” or “halogen” as used herein is intended to includechlorine, fluorine, bromine and iodine.

Unless specifically defined, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclic substituents may be or not substituted. For example,(C₁-C₆) alkyl may be substituted by one, two or three substitutentsselected from OH, halogen, alkoxyl, dialkylamino, or heterocyclic suchas morpholinyl, piperidinyl.

Included in the present invention is the free form of compounds ofFormula I, as well as the pharmaceutically acceptable salts andstereoisomers thereof. Some of the specific compounds exemplified hereinare the protonated salts of amine compounds. The term “free form” refersto the amine compounds in non-salt form. The encompassedpharmaceutically acceptable salts not only include the salts exemplifiedfor the specific compounds described herein, but also all the typicalpharmaceutically acceptable salts of the free form of compounds ofFormula I. The free form of the specific salt compounds described may beisolated using techniques known in the art. For example, the free formmay be regenerated by treating the salt with a suitable dilute aqueousbase solution such as dilute aqueous NaOH, potassium carbonate, ammoniaand sodium bicarbonate. The free forms may differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the acid and base salts are otherwisepharmaceutically equivalent to their respective free forms for purposesof the invention.

The pharmaceutically acceptable salts of the present invention may besynthesized from the compounds of the present invention which contain abasic or acidic moiety by conventional chemical methods. Generally, thesalts of the basic compounds are prepared either by on exchangechromatography or by making the free base react with stoichiometricamounts or with an excess of the desired salt-forming inorganic ororganic acid in a suitable solvent or various combinations of solvents.Similarly, the salts of the acidic compounds are formed by reactionswith the appropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of the presentinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by making a basic instant compound react withan inorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroaceticand the like.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N1-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like.

It will be noted that, the compounds of the present invention arepotentially internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom.

The present invention relates to deuterated benzopyran compounds havingstructure features as shown in Formula (I). With excellentanti-inflammatory and analgesic effects and the capability to inhibitgrowth of tumor cells, such compounds are novel COX-2 selectiveinhibitors. The compounds and pharmaceutically acceptable salts thereofdisclosed by the present application can be applied in preparinganti-inflammatory and analgesic drugs and drugs for treating orpreventing tumors.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The compounds of the present invention may be prepared by using thefollowing reactions besides the methods which have been published inarticles or well validated in the experimental procedures. Therefore,the synthetic solutions below are just illustrative and not intended tolimit the compounds or any specific substituent. The number of thesubstituents in the solution does not need to comply with the numberspecified in the Claims. Furthermore, for clear, the Formula (I) showinga single substitution may allow compounds with multiple substituents.

Solutions

As shown in Solution A, compounds in Formula (I) may be synthesized bythree steps by using deuterated phenol as the starting material.

Solution A

The compounds and pharmaceutically acceptable salts thereof designed inthe present application may be used with other traditionalanti-inflammatory drugs both available or under development, forexample, drugs such as steroid anti-inflammatory drugs, non-steroidanti-inflammatory drugs, iNOS inhibitors, LTB4 receptor stimulants andLTA4 hydrolase inhibitors, to enhance the anti-inflammatory andanalgesic effects, or, may be used with antibiotics, alkylated drugs,antimetabolites, hormone drugs, immuno drugs, interferon drugs and someother combinations of drugs to enhance the treatment or inhibitioneffects to tumors.

Administration and Dose Ranges

Based on the standard pharmaceutical technology, the compounds of thepresent invention may be administrated alone or in pharmaceuticalcombinations with pharmaceutically acceptable receptors, accessories ordiluents to mammals, preferably human beings, for example, by oral,subcutaneous. Intraperitoneal, intravenous, rectal, topical, ocular,pulmonary, nasal and parenteral.

When compounds of Formula (I) are used in cancer patients foranti-inflammatory and analgesic purposes or treatment, the oral dose is0.1-500 mg/day/kg administrated in a single dose daily, or in two,three, four or some other times a day, or in sustained release forms.For most large mammals, the dose is preferably 0.1-1500 mg/day/kg, morepreferably 0.5-100 mg/day/kg. For patients of average weight of 70 kg,the daily dose is 1-100 mg/day/kg. For some particularly highly activecompounds, the daily dose for adults may be as low as 0.1 mg/day.

Preparations:

The pharmaceutical compositions containing active ingredients may be ina form suitable for oral administration, for example, tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal administration may be prepared according to any method known in theart of the manufacture of pharmaceutical compositions, and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be,for example, inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, microcrystalline cellulose,sodium crosscarmelose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropyl-methylcellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate butyrate may be employed. The dose oftablets may be 0.1 mg/tab, 0.2 mg/tab, 0.25 mg/tab, 0.5 mg/tab, 1mg/tab, 2 mg/tab, 5 mg 10 mg/tab, 25 mg/tab, 50 mg/tab, 100 mg/tab and250 mg/tab. The dose of other forms, such as capsulates, may bereferenced similarly.

Formulations for oral use may also be presented as hard gelatin capsuleswhere the active Ingredients are mixed with inert solid diluents, forexample, calcium carbonate, calcium phosphate or kaolin, or, as softgelatin capsules where the active ingredients are mixed with watersoluble carriers such as polyethyleneglycol or an oil medium, forexample peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentssuch as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain thickening agents, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredients inadmixture with dispersing or wetting agent, suspending agent and one ormore preservatives. Suitable dispersing or wetting agents and suspendingagents have been exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the present invention may also be ina form of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain demulcents, preservatives, flavoring agents, coloringagents and antioxidants.

The pharmaceutical compositions may be in a form of sterile injectableaqueous solutions. Among the acceptable carriers and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredients are dissolved inthe oily phase. For example, the active ingredients may be firstdissolved in a mixture of soybean oil and lecithin. The oil solution isthen introduced into a water and glycerol mixture and processed to formmicroemulations.

The injectable solutions or microemulsions may be introduced into apatient's blood stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An embodiment ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in a form of a sterile injectableaqueous or oleagenous suspension for intramuscular and subcutaneousadministration. This suspension may be formulated according to the knownart using those suitable dispersing or wetting agents and suspendingagents which have been mentioned above. The sterile injectablepreparation may also be a sterile injectable solution or suspension in anon-toxic parenterally acceptable diluent or solvent, for example as asolution in 1,3-butane diol. In addition, nonvolatile oils areconventionally employed as a solvent or suspending medium. For thispurpose, any bland nonvolatile oil may be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid finduse in the preparation of injectables.

Compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at normal temperature but liquid at the rectaltemperature and will therefore melt in the rectum to release the drug.Such materials include cocoa butter, glycerinated gelatin, hydrogenatedvegetable oils, mixtures of polyethylene glycols of various molecularweights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds of the present invention may be administered in intranasalform via topical use of suitable intranasal carriers and deliverydevices, or via transdermal routes, using those forms of transdermalskin patches well known to those of ordinary skill in the art. To beadministered in the form of a transdermal delivery system, the doseadministration will, of course, be continuous rather than intermittentthroughout the dose regimen. The compounds of the present invention mayalso be delivered as a suppository employing bases such as cocoa butter,glycerinated gelatin, hydrogenated vegetable oils, mixtures ofpolyethylene glycols of various molecular weights and fatty acid estersof polyethylene glycol.

When the compounds of the present invention are administered to a humansubject, the daily dose will normally be determined by the prescribingphysician with the dose generally varying according to the age, weight,sex and response of the individual patient, as well as the severity ofthe patient's symptoms.

Metabolites and Prodrugs:

The metabolites of the compounds and pharmaceutically acceptable saltsthereof disclosed in the present invention, and prodrugs that may beconverted to the compounds and pharmaceutically acceptable salts thereofdisclosed in the present invention are encompassed in the claims of thepresent application.

Combined Therapy:

The compounds of Formula I may be used in combination with other drugswhich have been known to be useful in the treatment or amelioration ofthe diseases or similar diseases. In the combined administration, suchother drugs may be administered, by a route administration and in a dosecommonly used, and contemporaneously or sequentially with the compoundsof Formula I. When the compounds of Formula I are used contemporaneouslywith one or more other drugs, a pharmaceutical composition containingone or more other known drugs and the compounds of Formula I ispreferred. The combined therapy also includes therapies in which thecompounds of Formula I and one or more other known drugs areadministered on overlapping schedules. When used in combination with oneor more other drugs, the compounds of Formula I and the other knowndrugs may be used in a lower dose than when they are used alone.

Drugs or active ingredients which may be used in combination with thecompounds of Formula I include but are not limited to:

1) traditional steroid anti-inflammatory and analgesic drugs, forexample, Dexamethasone, Diethyistilestrol;

2) non-steroid anti-inflammatory and analgesic drugs, for example,Diclofenac, Chlorfenamic Acid, Analgin, Amino beaver, Aspirin,Butazodine, Piroxicam, Indometacin, Naproxen, Ibuprofen, Piroxicam,Celecoxib, Nabumetone, Ketoprofen, Ketorolac, Tetraclofenamic acid,Sulindac, Magnesium salicylate, Natrium salicylicum, Magnesium cholinesalicylate, Diflunisal, Sasapyrine;

3) LTB₄ receptor antagonist, for example, CGS-25019C, ETH-615, T-0757,LY-213024, LY-210073, LY223982, LY233469, ONO-LB457, ONO-4057,ONO-LB-448, SC-53228, SC-41930, SC-50605, SC-51146, SB-209247;

4) 5-LO inhibitors, for example, A-76745, 78773, ABT761, CMI-392,E-3040. ML-3000, PF-5901, EF-40, F-1322, ML-3000, R-840;

5) iNOS inhibitors;

6) LTA4 hydrolase inhibitors, for example, RP-64966;

7) Mu receptor antagonist;

8) Kappa receptor antagonist;

9) neurokinins receptor antagonist;

10) antibiotic anticancer drugs, for example, Taiho 4181-A, TakedaTAN-868A, Fujisawa FK-973, Bristol-Myers BL-6859, KM-5539, KT-5432;

11) alkylation of anticancer drugs, for example, Shionogi 254-S, SanofiCY-233, Degussa D-19-384, NCI NSC-164395, NCI NSC-342215, ProterPTT-119;

12) antimetabolite drugs, for example, Lilly DATHF, Lilly LY-188011,Lilly LY-264618, NCI NSC-127716, NCI NSC-164880, NCI NSC-39661, NCINSC-612567;

13) hormonal anticancer drugs;

14) immune anticancer drugs;

15) interferon anticancer drugs;

16) radioprotector, for example, AD-5, 1-201, MM-159, WR-151327,FUT-187;

17) some other mixed anticancer drugs, for example, Biotec AD-5, KyorinAHC-52, Ajinomoto CDAF, Chemex CHX-100, Merz D-609;

The above combinations include combinations of the compounds of FormulaI not only with one of drugs mention above, but also with two or morethan two of these drugs.

The present invention will be further explained as below by embodiments.

Embodiment 1

6-(methyl-D3)-2-(trifluoromethyl)-2H-chromence-3-carboxylic acid

Step 1: 2-hydroxy-5-(methyl-D3)-benzaldehyde

4-(methyl-D3)-phenol (0.90 g, 8.1 mmol) was dissolved intotrifluoroacetic acid (6 mL) and then slowly added withhexamethylenetetramine (1.3 g, 9.6 mmol). The system was reacted at 80°C. for 1 hr, cooled to room temperature, added with water (6 mL) andthen stirred for 0.5 hrs. At the end of reaction, saturated sodiumbicarbonate solution was added and extracted with ethyl acetate, and theorganic phase was washed with brine, dried and evaporated in vacuum toobtain 0.30 g of the product (27%) by column chromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 10.74 (s, 1H), 9.77 (s, 1H), 7.24 (d,2H),6.80 (s, 1H)

Step 2: 6-(methyl-D3)-2-(trifluoromethyl)-2H-chromence-3-carboxylate

The resulting product (0.25 g, 1.8 mmol) from step 1, anhydrous K₂CO₃(0.25 g, 1.8 mmol) and ethyl 4,4,4-trifluorocrotonate (1.2 g, 7.2 mmol)were mixed in DMF (10 mL), and then the system was heated to 85° C. forreaction for 2 hrs. At the end of reaction, the reaction system wascooled to room temperature and added with water, the mixture wasextracted with ethyl acetate, and the organic phase was dried andevaporated in vacuum to obtain 0.39 g of the product (76%) by columnchromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 7.88 (s, 1H), 7.31 (s, 1H), 7.20 (d, 1H),6.92 (d, 1 H), 5.91(m, 1H), 4.24(dd,2H), 1.26(t,3H)

MS (MM-ES+APCI), m/z: 290 (M+H⁺)

Step 3: 6-(methyl-D3)-2-(trifluoromethyl-2H-chromence-3-carboxylic acid

The resulting product (0.3 g, 1.0 mmol) from step 2 was dissolved into asolution (20 mL, alcohol/water=10/1), then slowly added with NaOH (0.12g, 3.0 mmol), and stirred at room temperature overnight. At the end ofreaction, t the reaction system was evaporated to remove alcohol,adjusted pH to 3 and extracted with ethyl acetate/water, and the organicphase was dried and evaporated in vacuum to obtain 0.14 g of the product(54%).

¹HNMR (400 MHz, d₆-DMSO), δ 7.80 (s, 1H), 7.28 (s, 1H), 7.18 (d, 1H),6.91 (d, 1H), 5.83(m, 1H)

MS (MM-ES+APCI), m/z: 260 (M−H⁺)

Embodiment 2

8-(ethyl-D5)-6-(trifluoromethoxy)-2-(trifluormethyl)-2H-Chromene-3-carboxylicacid

Step 1: 2-hydroxy-3-iodo-5-(trifluoromethoxy) benzaldehyde

2-hydroxy-5-(trifluoromethoxy) benzaldehyde (2.0 g, 9.7 mmol) wasdissolved into DMF (20 mL) and then added with NIS (5.4 g, 24 mmol) inbatches. The mixture was stirred for 2 days at room temperature. At theend of reaction, saturated sodium thiosulfate solution was added andextracted with ethyl acetate, and the organic phase was dried andevaporated in vacuum to obtain the product (0.30 g, 78%) by columnchromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 11.75 (s, 1H), 9.71 (s, 1H), 7.84 (d, 1H),7.42 (s, 1H)

MS (MM-ES+APCI), m/z: 331 (M−H⁺)

Step 2: ethyl8-iodo-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate

The resulting product (2.5 g, 7.5 mmol) from step 1, triethylamine (2mL) and ethyl 4,4,4-trifluorocrotonate (5.1 g, 30 mmol) were mixed inDMF (10 mL), and then the system was heated to 85° C. for reaction for48 hrs. At the end of reaction, the reaction system was cooled to roomtemperature, added with water and extracted with ethyl acetate, and theorganic phase was dried and evaporated in vacuum to obtain 2.5 g of theproduct (69%) by column chromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 7.60 (s, 2H), 7.10 (s, 1H), 5.81 (m, 1H),4.30(dd, 2H), 1.33(m,3H)

MS (MM-ES+APCI), m/z: 481 (M−H⁺)

Step 3: ethyl6-(trifluoromethoxy-2-(trifluoromethyl)-8-((trimethylsilyl)ethynyl)-2H-chromen-3-carboxylate

The resulting product (2.5 g, 5.2 mmol) from step 2, CuI (0.29 g, 1.5mmol), tetra(triphenylphosphine) palladium (0.60 g, 0.50 mmol) andtriethylamine (1.2 mL) were mixed in toulene (20 mL), and the system wasstirred for 2 days at room temperature under the protection of nitrogen.At the end of reaction, the reaction system was added with water andthen extracted with ethyl acetate, and the organic phase was dried andevaporated in vacuum to obtain 2.2 g of the product (94%) by columnchromatography.

MS (MM-ES+APCI), m/z: 453 (M+H⁺)

Step 4: ethyl8-(ethynyl-D1)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate

The resulting product (2.3 g, 5.0 mmol) from step 3 and K₂CO₃ (1.4, 10mmol) were added in alcohol (20 mL), and the system was stirred for 30min at room temperature and then added with 120 (20 mL). The mixedsolution was extracted with ethyl acetate, and the organic phase wasdried and evaporated in vacuum to obtain 1.5 g of the product (79%) bycolumn chromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 7.65 (s, 1H), 7.31 (s, 1H), 7.09 (s, 1H),5.79 (m, 1H), 4.35(dd,2H), 1.27(t,3H)

MS (MM-ES+APCI), m/z: 382 (M+H⁺)

Step 5: ethyl8-(ethyl-D5)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate

A sealed bottle was added with the resulting product (0.90 g, 2.4 mmol)from step 4, Pd/C (0.1 g) and ethyl acetate (1.2 mL) and then passedthrough with 02 for replacement until the sealed bottle was filled upwith D₂ (30 Psi). The system was reacted for 1 hr at room temperatureand then filtered with kieselguhr, and the filtrate was dried andevaporated in vacuum to obtain 0.9 g of the product (96%) by columnchromatography.

MS (MM-ES+APCI), m/z: 390 (M+H⁺)

Step 6:8-(ethyl-d5)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylicacid

The resulting product (0.9 g, 2.3 mmol) from step 5 was dissolved inmixed solution (30 mL, tetrahydrofuran/methanol/water=10/1/1), and thesolution was slowly added with NaOH (0.9 g, 24 mmol) and then stirredovernight at room temperature. At the end of reaction, the reactionsystem was evaporated to remove methanol, then adjusted pH to 3 andextracted with ethyl acetate, and the organic phase was dried andevaporated in vacuum to obtain 0.5 g of the product (62%).

¹HNMR (400 MHz, d-CDCl₃), δ 7.79 (s, 1H), 7.08 (s, 1H), 6.98 (s, 1H),5.73(m, 1H)

MS (MM-ES+APCI), m/z: 360 (M−H⁺)

Embodiment 3

6-chloro-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylicacid

Step 1: 1-methoxy-3, 5-dimethylbenzene

3,5-xylenol (10 g, 0.082 mol) and anhydrous potassium carbonate (34 g,0.25 mol) were added into DMF (150 mL) and then iodomethane (12.8 g,0.090 mmol) was dropped under an ice bath. The system was stirredovernight at room temperature. At the end of reaction, the reactionsystem was added with water and then extracted with ethyl acetate, andthe organic phase was washed with saturated brine, then dried andevaporated in vacuum to obtain 10 g of the product (90%) by columnchromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 6.60(s, 1H), 6.53 (s, 2H), 3.77 (s, 3H),2.29 (s, 6H)

Step 2: 1-methoxy-3,5-(dimethyl-D6)-benzene

The resulting product (6.0 g, 0.044 mol) from step 1, potassiumtert-butoxide (20 g, 0.18 mol) and deuterated DMSO (15 mL) were addedinto a single-neck bottle, and the system was replaced with argon andthen reacted at 120□ for 3 hrs. The reaction system was cooled to roomtemperature, added with a proper amount of deuterium oxide, oscillatedand extracted with ethyl acetate. The organic phase was washed withwater, dried and evaporated in vacuum. The obtained liquid was treatedagain and the post-treatment operations were repeated to obtain 5 g ofthe product (80%).

¹HNMR (400 MHz, d₆-DMSO), δ 6.56(s, 1H), 6.53 (s, 1H), 3.7(s, 3H)

Step 3: 3,5-(dimethyl-D6)-phenol

The resulting product (5 g, 0.035 mol) from step 2 was dissolved inanhydrous dichloromethane (20 mL) and then dropwise added withdichloromethane solution (20 mL) of boron tribromide (17.6 g, 0.070 mol)under an ice bath, after dropping, the system continued to be stirredfor 2 hrs. At the end of reaction, the reaction system was poured intoice water and then extracted with ethyl acetate, and the organic phasewas washed with saturated brine, dried and evaporated in vacuum toobtain 4 g of the product (89%) by column chromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 9.06(s, 1H), 6.40 (s, 1H), 6.36(s, 1H)

Step 4: 4-chloro-3,5-(dimethyl-D6)-phenol

The resulting product (1.2 g, 9.4 mmol) from step 3 and SO₂Cl₂ (1.27,9.4 mmol) were added in CCl₄ (20 mL), and the system was refluxed for 5hrs and then evaporated in vacuum to obtain 1 g of the product (65%) bycolumn chromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 9.37(s, 1H), 6.57 (s, 2H)

Step 5: 3-chloro-6-hydroxy-2,4-(dimethyl-D6)-benzaldehyde

The resulting product (1.0 g, 6.2 mmol) from step 4 was dissolved intrifluoroacetic acid (10 mL), and the system was stirred for 1 hr at 80°C. and then slowly added with hexamethylenetetramine (1 g, 7.1 mmol).The system was reacted at 80° C. for 1 hr, cooled to room temperature,added with 10 mL of water and then stirred for 0.5 hrs. At the end ofreaction, saturated sodium bicarbonate solution was added and extractedwith ethyl acetate, and the organic phase was washed with brine, driedand evaporated in vacuum to obtain 0.50 g of the product (42%) by columnchromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 11.39(s, 1H), 10.36 (s, 1 H), 6.86 (s, 1 H)

Step 6: ethyl6-chloro-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylate

The resulting product (0.50, 2.6 mmol) from step 5, ethyl4,4,4-trifluorocrotonate (1.7 g, 10.1 mmol) and anhydrous potassiumcarbonate (0.36 g, 5.6 mmol) were dissolved in DMF (20 mL), and then thesystem was stirred for 2 hrs at 90° C. At the end of reaction, thereaction system was cooled to room temperature and added with water, themixture was extracted with ethyl acetate, and the organic phase wasdried and evaporated in vacuum to obtain 0.60 g of the product (67%) bycolumn chromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 7.98(s, 1H), 7.01 (s, 1H), 6.0 (m, 1H), 4.28(dd, 2H), 1.27 (t, 3H)

MS (MM-ES+APCI), m/z: 342(M+H⁺)

Step 7: ethyl6-chloro-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylicacid

The resulting product (0.60 g, 1.76 mol) from step 6, sodium hydroxide(704 mg, 17.6 mmol), alcohol (20 mL) and water (2 mL) were added into asingle-neck bottle, and the system was stirred overnight at roomtemperature. At the end of reaction, the reaction system was evaporatedto remove alcohol, then adjusted pH to 3 and extracted with ethylacetate. The organic phase was washed with saturated brine, dried andevaporated in vacuum to obtain 0.50 g of the product (91%).

¹HNMR (400 MHz, d-CDCl₃), δ 8.09(s, 1H), 6.81 (s, 1H), 5.63 (m, 1H)

MS (MM-ES+APCI), m/z: 312(M−H⁺)

Embodiment 4

6-bromo-5,7-(dimethyl-D6)-2-(trifluormethyl)-2H-chromene-3-carboxylicacid

Step 1: 1-methoxy-3, 5-dimethylbenzene

3,5-xylenol (10 g, 0.082 mol) and anhydrous potassium carbonate (34 g,0.25 mol) were added into DMF (150 mL) and then iodomethane (12.8 g,0.090 mmol) was dropped under an ice bath. The system was stirredovernight at room temperature. At the end of reaction, the reactionsystem was added with water and then extracted with ethyl acetate, andthe organic phase was washed with saturated brine, then dried andevaporated in vacuum to obtain 10 g of the product (90%) by columnchromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 6.60(s, 1H), 6.53 (s, 2H), 3.77 (s, 3H),2.29 (s, 6H)

Step 2: 1-methoxy-3,5-(dimethyl-D6)-benzene

The resulting product (6.0 g, 0.044 mol) from step 1, potassiumtert-butoxide (20 g, 0.18 mol) and deuterated DMSO (15 mL) were addedinto a single-neck bottle, and the system was replaced with argon andthen reacted at 120° C. for 3 hrs. The reaction system was cooled toroom temperature, added with a proper amount of deuterium oxide,oscillated and extracted with ethyl acetate. The organic phase waswashed with water, dried and evaporated in vacuum. The obtained liquidwas treated again and the post-treatment operations were repeated toobtain 5 g of the product (80%).

¹HNMR (400 MHz, d₆-DMSO), δ 6.56(s, 1H), 6.53 (s, 1H), 3.7(s,3H)

Step 3: 4-bromo-3,5-(dimethyl-D6)-phenol

Under the anhydrous conditions, in a single-neck bottle, the resultingproduct (1.0 g, 8.0 mol) from step 2 was dissolved in dichloromethane(10 mL) and then dropwise added with dichloromethane solution (10 mL) ofboron tribromide (4.0 g, 16 mmol) under an ice bath, after dropping, thesystem continued to be stirred for 2 hrs. At the end of reaction, thereaction system was poured into ice water and then extracted with ethylacetate, and the organic phase was washed with saturated brine, driedand evaporated in vacuum to obtain 1.3 g of the product (80%) by columnchromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 9.06(s, 1H), 6.39 (s, 1 H), 6.36 (s, 1H)

Step 4: 3-bromo-6-hydroxy-2,4-(dimethyl-D6)-benzaldehyde

The resulting product (0.50 g, 2.4 mmol) from step 3 was dissolved intrifluoroacetic acid (5 mL) and then slowly added withhexamethylenetetramine (0.41 g, 2.9 mmol). The system was reacted at 80°C. for 1 hr, cooled to room temperature, added with 10 mL of water andthen stirred for 0.5 hrs. At the end of reaction, saturated sodiumbicarbonate solution was added and extracted with ethyl acetate, and theorganic phase was washed with brine, dried and evaporated in vacuum toobtain 0.45 g of the product (79%) by column chromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 11.9(s, 1H), 10.03 (s, 1H), 7.77(s, 1H),7.69(s, 1H)

Step 5: ethyl6-bromo-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylate

The resulting product (0.45 g, 1.9 mmol) from step 4, ethyl4,4,4-trifluorocrotonate (1.3 g, 7.6 mmol) and anhydrous potassiumcarbonate (2.6 g, 1.9 mmol) were dissolved in DMF (10 mL), and then thesystem was stirred for 2 hrs at 90° C. At the end of reaction, thereaction system was cooled to room temperature and added with water, themixture was extracted with ethyl acetate, and the organic phase wasdried and evaporated in vacuum to obtain 0.40 g of the product (55%) bycolumn chromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 7.88(s, 1H), 6.76 (s, 1H), 5.7(m, 1H),4.3(dd, 2H), 1.35(t, 3H)

MS (MM-ES+APCI), m/z: 384 (M−H⁺)

Step 6: ethyl6-bromo-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylicacid

The resulting product (0.4 g, 1.3 mol) from step 5, sodium hydroxide(0.52 g, 13 mol), alcohol (20 mL) and water (2 mL) were added into asingle-neck bottle in turn, and the system was stirred overnight at roomtemperature. At the end of reaction, the reaction system was adjustedwith 7% of hydrochloric acid until pH to 7, and extracted with ethylacetate. The organic phase was washed with saturated brine, dried andevaporated in vacuum to obtain 0.30 g of the product (84%).

¹HNMR (400 MHz, d-CDCl₃), δ 8.01(s, 1H), 6.78 (s, 1H), 5.77(m, 1H)

MS (MM-ES+APCI), m/z: 356 (M−H⁺)

Embodiment 5

6-chloro-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

Step 1: 1-methoxy-2-methylbenzene

o-cresol (3.0 g, 0.028 mol) and anhydrous potassium carbonate (7.7 g,0.056 mol) were dissolved into 50 ml of DMF and then iodomethane (3.9 g,0.028 mmol) was dropped under an ice bath. The system was stirredovernight at room temperature. At the end of reaction, the reactionsystem was added with water and then extracted with ethyl acetate, andthe organic phase was washed with saturated brine, then dried andevaporated in vacuum to obtain 3 g of the product (89%) by columnchromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 7.15(m, 2H), 6.92 (d, 1H), 6.84 (m, 1H),3.77 (s, 3H), 2.10(s,3H)

Step 2: 1-methoxy-2-(methyl-D3)-benzene

The resulting product (3 g, 0.024 mol) from step 1, potassiumtert-butoxide (10.8 g, 0.096 mol) and deuterated DMSO (15 mL) were addedinto a single-neck bottle, and the system was replaced with argon andthen reacted at 120° C. for 3 hrs. The reaction system was cooled toroom temperature, added with a proper amount of deuterium oxide,oscillated and extracted with ethyl acetate. The organic phase waswashed with water, dried and evaporated in vacuum to obtain 1 g of theproduct (33%).

¹HNMR (400 MHz, d₆-DMSO), δ 7.15(m, 2H), 6.92 (d, 1H), 6.84 (m, 1H),3.77 (s, 3H)

Step 3: 4-chloro-1-methoxy-2-(methyl-D3)-benzene

The resulting product (1.0 g, 8 mmol) from step 2 and SO₂Cl₂ (2.16 g, 16mmol) were mixed in CCl₄ (30 mL), and the system is refluxed for 5 hrand evaporated in vacuum to obtain 1 g of the product (78%) by columnchromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 7.09(d, 2H), 6.80 (d, 1H), 3.80(s, 3H)

Step 4: 4-chloro-2-(methyl-D3)-phenol

Under the anhydrous conditions, in a single-neck bottle, the resultingproduct (1.0 g, 6.3 mol) from step 3 was dissolved in dichloromethane(10 mL) and then dropwise added with dichloromethane solution (10 mL) ofboron tribromide (1.6 g, 12.6 mmol) under an ice bath, after dropping,the system continued to be stirred for 4 hrs. At the end of reaction,the reaction system was poured into ice water and then extracted withdichloromethane, and the organic phase was washed with saturated brine,dried and evaporated in vacuum to obtain 0.8 g of the product (87%) bycolumn chromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 7.11(s, 1H), 7.06(d, 1H), 6.70(d,1H)

Step 5: 5-chloro-2-hydroxy-3-(methyl-D3)-benzaldehyde

The resulting product (0.80 g, 5.5 mmol) from step 4 was dissolved intrifluoroacetic acid (5 mL) and then slowly added withhexamethylenetetramine (0.92 g, 6.6 mmol). The system was reacted at 80°C. for 1 hr, cooled to room temperature, added with 10 mL of water andstirred for 0.5 hrs. At the end of reaction, saturated sodiumbicarbonate solution was added and extracted with ethyl acetate, and theorganic phase was washed with brine, dried and evaporated in vacuum toobtain 0.55 g of the product (57%) by column chromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 11.18(s, 1H), 9.84 (s, 1 H), 7.55(d, 2H)

Step 6: ethyl6-chloro-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylate

The resulting product (0.50, 2.6 mmol) from step 5, ethyl4,4,4-trifluorocrotonate (1.7 g, 10.1 mmol) and anhydrous potassiumcarbonate (0.36 g, 5.6 mmol) were dissolved in DMF (20 mL), and then thesystem was stirred for 2 hrs at 90° C. At the end of reaction, thereaction system was cooled to room temperature and added with water, themixture was extracted with ethyl acetate, and the organic phase wasdried and evaporated in vacuum to obtain 0.50 g of the product (50%) bycolumn chromatography.

¹HNMR (400 MHz, d-CDCl₃), δ 7.65(s, 1H), 7.16 (s, 1H), 7.07(s, 1H),5.73(m, 1H), 4.30(m, 2H), 1.27(m,3H)

Step 7:6-chloro-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The resulting product (0.50 g, 1.54 mol) from step 6, sodium hydroxide(624 mg, 15.6 mmol), alcohol (20 mL) and water (2 mL) were added in asingle-neck bottle, and the system was stirred overnight at roomtemperature. At the end of reaction, the reaction system was evaporatedto remove alcohol, then adjusted pH to 3 and extracted with ethylacetate. The organic phase was washed with saturated brine, dried andevaporated in vacuum to obtain 0.40 g of the product (88%).

¹HNMR (400 MHz, d₆-DMSO), δ 13.4(s, 1H), 7.84 (s, 1H), 7.46(s, 1H),7.35(s, 1H), 5.96(m, 1H)

Embodiment 6

6-bromo-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

Step 1: 1-methoxy-2-methylbenzene

o-cresol (5 g, 0.046 mol) and anhydrous potassium carbonate (19.17 g,0.14 mol) were dissolved into DMF (75 mL) and then iodomethane (6.65 g,0.048 mmol) was dropped under an ice bath. The system was stirredovernight at room temperature. At the end of reaction, the reactionsystem was added with water and then extracted with ethyl acetate, andthe organic phase was washed with saturated brine, then dried andevaporated in vacuum to obtain the product 4.72 g (83.5%) by columnchromatography.

MS (MM-ES+APCI), m/z: 123 (M⁺+H⁺)

Step 2: 1-methoxy-2-(methyl-D3)-benzene

The resulting product (1 g, 8.02 mmol) from step 1, potassiumtert-butoxide 3.68 g (33.0 mmol) and deuterated DMSO (2.5 mL) were addedinto a single-neck bottle, and the system was replaced with argon andthen reacted at 120° C. for 3 hrs. The reaction system was cooled toroom temperature, added with a proper amount of deuterium oxide,oscillated and extracted with ethyl acetate. The organic phase waswashed with brine, dried and evaporated in vacuum. The obtained liquidwas treated again and the post-treatment operations were repeated toobtain the product 0.85 g (83%).

¹HNMR (400 MHz, d₆-DMSO), δppm 7.15 (m, 2H), 6.92 (d, 1H, J=0.4 Hz),6.84 (d, 1H, J=22.4 Hz), 3.77 (s,3H)

Step 3: 4-bromo-2-(methyl-D3)-phenol

The resulting product (0.85 g, 6.8 mmol) from step 2 was dissolved inanhydrous dichloromethane (20 mL) and then dropwise added withdichloromethane solution (25 mL) of boron tribromide (1.6 g, 12.6 mmol)under an ice bath, and the system was stirred for 2 hrs at roomtemperature. At the end of reaction, the reaction system was poured intoice water and then extracted with dichloromethane, and the organic phasewas washed with saturated brine, dried and evaporated in vacuum toobtain the product 0.68 g (53%) by column chromatography.

¹HNMR (400 MHz; d-CDCl₃), δppm 7.24(s, 1H), 7.17(d, 1H,J=10.8 Hz),6.65(d, 1H,J=8.4 Hz)

Step 4: 5-bromo-2-hydroxy-3-(methyl-D3)-benzaldehyde

The resulting product (0.68 g, 3.6 mmol) from step 3 was dissolved intrifluoroacetic acid (5 mL), and the system was stirred for 1 hr at 80°C. and then slowly added with hexamethylenetetramine (0.61 g, 4.3 mmol).The system was reacted at 80° C. for 1 hr, cooled to room temperature,added with 10 mL of water and stirred for 0.5 hrs. At the end ofreaction, saturated sodium bicarbonate solution was added and extractedwith ethyl acetate, and the organic phase was washed with brine, driedand evaporated in vacuum to obtain 0.219 of the product (26.7%) bycolumn chromatography.

¹HNMR (400 MHz, d₆-DMSO), δppm 10.88(s, 1H), 10.03(s, 1H), 7.77(s, 1H),7.67(s, 1H)

Step 5: ethyl6-bromo-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylate

The resulting product (0.21 g, 0.96 mmol) from step 4, ethyl4,4,4-trifluorocrotonate (0.65 g, 3.80 mmol) and anhydrous potassiumcarbonate (0.133 g, 0.96 mmol) added in a single-neck bottle weredissolved in DMF (10 mL), and then the system was stirred for 6 hrs at80° C. The system was added with water and then extracted with ethylacetate, and the organic phase was dried and evaporated in vacuum toobtain 100 mg of the product (28.2%) by column chromatography.

¹HNMR (400 MHz, d₆-DMSO), δppm7.91 (s, 1H), 7.63(s, 1H), 7.49(s, 1H),6.05(m, 1H), 4.25 (dd,2H,J=6 Hz), 1.27(t,3H)

Step 6: 6-bromo-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-carboxylicacid

The resulting product (100 mg, 0.27 mol) from step 5, sodium hydroxide(109 mg, 0.27 mmol), alcohol (2 mL) and water (0.2 mL) were added into asingle-neck bottle, and the system was stirred overnight at roomtemperature. At the end of reaction, the reaction system was adjusted pHto 3, and then extracted with ethyl acetate. The organic phase waswashed with saturated brine, dried and evaporated in vacuum to obtain 89mg of the product (96.1%).

¹HNMR (400 MHz, d₆-DMSO), δppm 7.82(s, 1H), 7.56(s, 1H), 7.46(s, 1H),5.95(m, 1H)

MS(MM-ES+APCI), m/z: 339 (M−H⁺)

Embodiment 7

6,8-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

Step 1: 1-methoxy-2,4-dimethylbenzene

2,4-dimethylphenol (7.5 g, 0.062 mol) and anhydrous potassium carbonate(25.4 g, 0.18 mol) were dissolved into DMF (75 mL) and then iodomethane(8.83 g, 0.062 mol) was dropped under an ice bath. The system wasstirred overnight at room temperature. At the end of reaction, thereaction system was added with water and then extracted with ethylacetate, and the organic phase was washed with saturated brine, thendried and evaporated in vacuum to obtain 7.11 g of the product (85%) bycolumn chromatography.

MS(MM-ES+APCI), m/z: 137 (M+H⁺)

Step 2: 1-methoxy-2,4-(dimethyl-D6)-benzene

The resulting product (5 g, 0.037 mol) from step 1, potassiumtert-butoxide (16.473 g, 0.15 mol) and deuterated DMSO (12 mL) wereadded into a single-neck bottle, and the system was replaced with argonand then reacted at 120° C. for 3 hrs. The reaction system was cooled toroom temperature, added with a proper amount of deuterium oxide,oscillated and extracted with ethyl acetate. The organic phase waswashed with water, dried and evaporated in vacuum. The obtained liquidwas treated again and the post-treatment operations were repeated toobtain 2.86 g of the product (54.7%).

¹HNMR (400 MHz, d₆-DMSO), δppm 6.93 (d, 1H,J=2 Hz), 6.90(s, 1H), 6.77(d,1H), 3.71(s,3H)

Step 3: 2,4-(dimethyl-D6)-phenol

The resulting product (5 g, 0.035 mol) from step 2 was dissolved inanhydrous dichloromethane (80 mL) and then dropwise added withdichloromethane solution (80 mL) of boron tribromide (17.6 g, 0.070 mol)under an ice bath, after dropping, the system continued to be stirredfor 4 hrs. At the end of reaction, the reaction system was poured intoice water and then extracted with dichloromethane, and the organic phasewas washed with saturated brine, dried and evaporated in vacuum toobtain 3.32 g of the product (73.6%) by column chromatography.

¹HNMR(400 MHz, d₆-DMSO), δppm8.87(s, 1H), 6.81(s, 1H), 6.73(d, 1H),6.60(d, 1H)

Step 4: 2-hydroxy-3,5-(dimethyl-D6)-benzaldehyde

The resulting product (3.32 g, 0.026 mol) from step 3 was dissolved intrifluoroacetic acid (20 mL), and the system was stirred for 1 hr at 80°C. and then slowly added with hexamethylenetetramine (4.37 g, 0.031mol). The system was reacted at 80° C. for 1 hr, cooled to roomtemperature, added with 10 mL of water and stirred for 0.5 hrs. At theend of reaction, saturated sodium bicarbonate solution was added andextracted with ethyl acetate, and the organic phase was washed withbrine, dried and evaporated in vacuum to obtain 2.04 g of the product(49.6%) by column chromatography.

¹HNMR(400 MHz, d₆-DMSO), δppm10.78(s, 1H), 9.98(s, 1H), 7.37(s, 1H),7.31(s, 1H)

Step 5: ethyl6,8-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylate

The resulting product (2.02 g, 0.013 mol) from step 4, ethyl4,4,4-trifluorocrotonate (4.30 g, 0.026 mol) and anhydrous potassiumcarbonate (1.76 g, 0.013 mol) were dissolved in DMF (70 mL), and thenthe system was stirred for 6 hrs at 80° C. At the end of reaction, thereaction system was cooled to room temperature, added with water andthen extracted with ethyl acetate, and the organic phase was dried andevaporated in vacuum to obtain 2.35 g of the product (60.1%) by columnchromatography.

¹HNMR(400 MHz, d₆-DMSO), δppm 7.84(s, 1H), 7.13(s, 1H), 7.09(s, 1H),5.94(m, 1H), 4.25(dd, 1H), 1.27 (t,3H)

Step 6: 6,8-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylicacid

The resulting product (2.35 g, 7.68 mmol) from step 5, sodium hydroxide(3 g, 76.8 mmol), alcohol (40 mL) and water (4 mL) were added into asingle-neck bottle in turn, and the system was stirred overnight at roomtemperature. At the end of reaction, the reaction system was adjusted pHto 3, and then extracted with ethyl acetate. The organic phase waswashed with saturated brine, dried and evaporated in vacuum to obtain1.61 g of the product (75.4%).

¹HNMR(400 MHz, d₆-DMSO), δppm 13.19(s, 1H), 7.77(s, 1H), 7.10(s, 1H),7.80(s, 1H), 5.88(m, 1H)

MS(MM-ES+APCI), m/z: 277 (M−H⁺)

Embodiment 8

8-chloro-6-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

Step 1: 1-methoxy-4-methylbenzene

p-cresol (20 g, 0.19 mol) and anhydrous potassium carbonate (75 g, 0.54mol) were added into DMF (500 mL) and then iodomethane (27 g, 0.19 mol)was dropped under an ice bath. The system was stirred overnight at roomtemperature. At the end of reaction, the reaction system was added withwater and then extracted with ethyl acetate, and the organic phase waswashed with saturated brine, then dried and evaporated in vacuum toobtain 20 g of the product (86%) by column chromatography.

MS(MM-ES+APCI), m/z: 123 (M+H⁺)

Step 2: 1-methoxy-4-(methyl-D3)-benzene

The resulting product (20 g, 0.16 mol) from step 1, potassiumtert-butoxide (76 g, 0.64 mol) and deuterated DMSO (60 mL) were addedinto a single-neck bottle, and the system was replaced with argon andthen reacted at 120° C. for 3 hrs. The reaction system was cooled toroom temperature, added with a proper amount of deuterium oxide,oscillated and extracted with ethyl acetate. The organic phase waswashed with water, dried and evaporated in vacuum. The obtained liquidwas treated again and the post-treatment operations were repeated toobtain 10 g of the product (50%).

MS(MM-ES+APCI), m/z: 126 (M+H⁺)

Step 3: 4-(methyl-D3)-phenol

The resulting product (2.0 g, 0.016 mol) from step 2 was dissolved inanhydrous dichloromethane (40 mL) and then dropwise added withdichloromethane solution (40 mL) of boron tribromide (8.0 g, 0.032 mol)under an ice bath, after dropping, the system continued to be stirredfor 2 hrs. At the end of reaction, the reaction system was poured intoice water and then extracted with dichloromethane, and the organic phasewas washed with saturated brine, dried and evaporated in vacuum toobtain 1 g of the product (58%) by column chromatography.

Step 4: 2-chloro-4-(methyl-D3)-phenol

The resulting product (1.0 g, 9.0 mmol) from step 3 and SO₂Cl₂ (1.2 g,9.0 mmol) were added in CCl₄ (20 mL), and the system was refluxed for 5hrs and then evaporated in vacuum to obtain 0.60 g of the product (46%)by column chromatography.

Step 5: 3-chloro-2-hydroxy-5-(methyl-D3)-benzaldehyde

The resulting product (0.60 g, 4.1 mmol) from step 4 was dissolved intrifluoroacetic acid (20 mL), and the system was stirred for 1 hr at 80°C. and then slowly added with hexamethylenetetramine (0.69 g, 4.9 mmol).The system was reacted at 80° C. for 1 hr, cooled to room temperature,added with 10 mL of water and then stirred for 0.5 hrs. At the end ofreaction, saturated sodium bicarbonate solution was added and extractedwith ethyl acetate, and the organic phase was washed with brine, driedand evaporated in vacuum to obtain 0.25 g of the product (35%) by columnchromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 10.9(s, 1H), 10.11 (s, 1H), 7.60 (s, 1H),7.52 (s, 1H)

Step 6: ethyl8-chloro-6-(methyl-D3)-2-(trifluormethyl)-2H-chromene-3-carboxylate

The resulting product (0.25 g, 1.4 mmol) from step 5, ethyl4,4,4-trifluorocrotonate (0.48 g, 2.8 mmol) and anhydrous potassiumcarbonate (0.46 g, 2.8 mmol) were dissolved in DMF (10 mL), and then thesystem was stirred for 3 hrs at 90° C. At the end of reaction, thereaction system was cooled to room temperature and added with water, themixture was extracted with ethyl acetate, and the organic phase wasdried and evaporated in vacuum to obtain 0.2 g of the product (44%) bycolumn chromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 7.39(s, 1H), 7.31 (s, 1H), 6.1 (m, 1H), 4.27(dd, 2H), 1.30 (t, 3H)

MS (MM-ES+APCI), m/z: 325 (M+H⁺)

Step 7:8-chloro-6-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The resulting product (020 g, 0.60 mmol) from step 6, sodium hydroxide(0.48 g, 12 mmol), alcohol (20 mL) and water (2 mL) were added into asingle-neck bottle, and the system was stirred overnight at roomtemperature. At the end of reaction, the reaction system was adjusted pHto 3 and extracted with ethyl acetate. The organic phase was washed withsaturated brine, dried and evaporated in vacuum to obtain 0.15 g of theproduct (85%).

¹HNMR (400 MHz, d-CDCl₃), δ 8.09(s, 1H), 6.81 (s, 1H), 5.63 (m, 1H)

MS (MM-ES+APCI), m/z: 395(M−H⁺)

Embodiment 9

6,8-dibromo-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylicacid

Step 1: 1-methoxy-3, 5-dimethyl-benzene

3,5-xylenol (10 g, 0.082 mol) and anhydrous potassium carbonate (34 g,0.25 mol) were added into DMF (150 mL) and then iodomethane (12.8 g,0.090 mol) was dropped under an ice bath. The mixture was stirredovernight at room temperature. At the end of reaction, the reactionsystem was added with water and then extracted with ethyl acetate, andthe organic phase was washed with saturated brine, then dried andevaporated in vacuum to obtain 10 g of the product (90%) by columnchromatography.

1HNMR (400 MHz, d-CDCl₃), δ 6.60(s, 1H), 6.53 (s, 2H), 3.77(s, 3H), 2.29(s, 6H)

Step 2: 1-methoxy-3,5-(dimethyl-D6)-benzene

The resulting product (6.0 g, 0.044 mol) from step 1, potassiumtert-butoxide (20 g, 0.18 mol) and deuterated DMSO (15 mL) were addedinto a single-neck bottle, and the system was replaced with argon andthen reacted at 120° C. for 3 hrs. The reaction system was cooled toroom temperature, added with a proper amount of deuterium oxide,oscillated and extracted with ethyl acetate. The organic phase waswashed with water, dried and evaporated in vacuum. The obtained liquidwas treated again and the post-treatment operations were repeated toobtain 5 g of the product (80%).

¹HNMR (400 MHz, d₆-DMSO), δ 6.56(s, 1H), 6.55(s, 1H), 6.53 (s, 1H),3.7(s, 3H)

Step 3: 4-bromo-3,5-(dimethyl-D6)-phenol

Under the anhydrous conditions, in a single-neck bottle, the resultingproduct (1.0 g, 8.0 mmol) from step 2 was dissolved in dichloromethane(10 mL) and then dropwise added with dichloromethane solution (10 mL) ofboron tribromide (4.0 g, 16 mmol) under an ice bath, after dropping, thesystem continued to be stirred for 2 hrs. At the end of reaction, thereaction system was poured into ice water and then extracted withdichloromethane, and the organic phase was washed with saturated brine,dried and evaporated in vacuum to obtain 1.3 g of the product (80%) bycolumn chromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 9.92(s, 1H), 6.58(s, 2H).

Step 4: 2,4-dibromo-3,5-(dimethyl-D6)-phenol

Under the anhydrous conditions, the resulting product (1 g, 4.83 mmol)from step 3 was dissolved in dichlormethane (10 mL) and then dropwiseadded with dichloromethane solution (5 mL) of liquid bromine (0.81 g,5.07 mmol) under an ice bath, after dropping, the system continued to bestirred overnight at room temperature. At the end of reaction, thereaction system was added with sodium hydrogen sulfite solution forremoving excessive bromine, evaporated to remove dichloromethane andextracted with ethyl acetate/water. The organic phase was washed withsaturated brine, dried and evaporated in vacuum to obtain 1.25 g of theproduct (90.5%) by column chromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 10.30(s, 1H), 6.82 (s, 1H)

Step 5: 3,5-dibromo-2-hydroxy-4,6-(dimethyl-D6)-benzaldehyde

The resulting product (0.50 g, 1.75 mmol) from step 4 was dissolved intrifluoroacetic acid (5 mL), and the mixture was slowly added withhexamethylenetetramine (0.29 g, 2.10 mmol). The system was reacted at80° C. for 1 hr, cooled to room temperature, added with 10 mL of waterand then stirred for 0.5 hrs. At the end of reaction, saturated sodiumbicarbonate solution was added and extracted with ethyl acetate, and theorganic phase was washed with brine, dried and evaporated in vacuum toobtain 0.34 g of the product (61.9%) by column chromatography.

¹HNMR (400 MHz, d₆-DMSO), δ 12.72(s, 1H), 10.30 (s, 1H)

Step 6: ethyl6,8-dibromo-5,7-(dimethyl-D6)-2-(trifluormethyl)-2H-chromene-3-carboxylate

The resulting product (0.34 g, 1.08 mmol) from step 5, ethyl4,4,4-trifluorocrotonate (0.72 g, 4.32 mmol) and anhydrous potassiumcarbonate (0.15 g, 1.08 mmol) were dissolved in DMF (6 mL), and then thesystem was stirred for 6 hrs at 90° C. At the end of reaction, thereaction system was cooled to room temperature and added with water, themixture was extracted with ethyl acetate, and the organic phase wasdried and evaporated in vacuum to obtain 0.12 g of the product (23.9%)by column chromatography.

1HNMR (400 MHz, d-CDCl₃), δ 7.95(s, 1H), 5.80(m, 1H), 4.34(dd, 2H),1.36(t, 3H)

Step 7:6,8-dibromo-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylicacid

The resulting product (0.12 g, 0.26 mmol) from step 6, sodium hydroxide(0.10 g, 2.6 mmol), alcohol (4 mL) and water (0.4 mL) were added into asingle-neck bottle, and the system was stirred overnight at roomtemperature. The reaction system was adjusted with 7% hydrochloric aciduntil pH to 7 and extracted with ethyl acetate. The organic phase waswashed with saturated brine, dried and evaporated in vacuum to obtain 43mg of the product (38.0%).

¹HNMR (400 MHz, d-CDCl₃), δ 8.08(s, 1H), 5.77(m, 1H)

MS (MM-ES+APCI), m/z: 435 (M−H⁺)

Embodiment 10

7-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 7.86(s, 1H), 7.13 (d, 1H), 7.00 (s, 1H),6.75 (d, 1H), 5.36 (m, 1H)

Embodiment 11

7-(hexyl-D13)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 7.92(s, 1H), 7.12 (d, 1H), 6.64 (d, 1H),6.62 (s, 1H), 5.43 (m, 1H)

Embodiment 12

6-chloro-7-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 8.03(s, 1H), 7.06 (s, 1H), 6.50 (s, 1H),5.46 (m, 1H)

Embodiment 13

8-(1-methylhexyl-D15)-2-trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 7.86(s, 1H), 7.46 (d, 1H), 7.27 (d, 1H),6.75 (m, 1H), 5.43 (m, 1H)

Embodiment 14

6-chloro-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 8.01(s, 1H), 6.85 (s, 1H), 6.77 (s, 1H),5.35 (m, 1H)

Embodiment 15

6-chloro-7-(1,1-dimethylhexyl-D17)-2-(trifluoromethyl)-2H-chromene-3-carboxylicacid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 7.95(s, 1H), 7.10 (s, 1H), 6.73 (s, 1H),5.51 (m, 1H)

Embodiment 16

6-chlor-8-(1-methylhexyl-D15)-2-(trifluoromethyl)-2H-chromene-3-carboxylicacid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 7.98 (s, 1H), 7.25 (s, 1H), 6.99 (s, 1H),5.41 (m, 1H)

Embodiment 17

7-(1-methylhexyl-D15)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ7.92(s, 1H), 7.09 (d, 1H), 6.65 (d, 1H), 5.48(m, 1H)

Embodiment 18

6-chloro-7-(hexyl-D13)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 8.05(s, 1H), 7.12 (s, 1H), 7.00 (s, 1H),5.48 (m, 1H)

Embodiment 19

8-(hexyl-D13)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 8.09(s, 1H), 7.48(d, 1H), 7.04(d, 1H), 6.78(m, 1H), 5.54 (m, 1H)

Embodiment 20

7,8-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 7.95 (s, 1H), 6.94 (d, 1H), 6.63 (d, 1H),5.56(m, 1H)

Embodiment 21

6-chloro-8-(hexy-D13)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid

The synthetic method refers to Embodiment 1.

¹HNMR (400 MHz, d-CDCl₃), δ 8.05(s, 1H), 7.24(s, 1H), 6.99 (s, 1H), 5.24(m, 1H)

Embodiment 22

Deuterated benzopyran compounds of different concentrations wereuniformly mixed with ovine COX-1 and human recombinant COX-2 forincubation for 15 min, respectively, and then the system was added withHeme and ADHP for incubation for another 2 min and finally added withsubstrate arachidonic acid. The light emission intensity of the reactionproduct at 595 nm was immediately detected by a microplate reader underexciting light at 530 nm. The results showed that deuterated benzopyrancompounds may significantly inhibit the enzyme reaction rate of COX-2and have good selectivity. In the whole blood assay, venous blood ofhealthy donors was collected with a non-anticoagulation tube and aheparin tube, deuterated benzopyran compounds of differentconcentrations (1×10⁻⁸ to 1×10⁻⁴) were mixed with the blood in thenon-anticoagulation tube, the supernatant was collected after the bloodwas coagulated and then measured by ELISA in terms of the yield of TXB2;and deuterated benzopyran compounds of different concentrations (1×10⁻⁸to 1×10⁻⁴) were mixed with the blood in the heparin tube, the mixturewas added with lipopolysaccharide until the final concentration was 100μg/mL, mixed uniformly and then kept stand overnight at 37° C., thesupernatant was collected by centrifugation and then measured by ELISAin terms of the yield of PGE2. According to the inhibition effects ofthe deuterated benzopyran compounds on the two isomerases and theinhibition effects of the deuterated benzopyran compounds on TXB2/PGE2in the blood, 50% inhibitory concentration (IC50) values are calculatedas shown in Table 1. (The used compounds were compounds prepared inEmbodiments 1-9 and expressed by Drug No. in Table 1, and GIBH-1006,GIBH-1004, GIBH-1016, GIBH-1008, GIBH-1010, GIBH-1012, GIBH-1014,GIBH-1018 and GIBH-1051 were corresponding to the compounds prepared inEmbodiments 1-9, respectively.)

TABLE 1 Inhibition IC50 of part of compounds onto two isomerases COXsand inhibition IC50 onto generation of TXB2/PGE2 in the whole blood testDrug No. COX-1 COX-2 TXB2 PGE2 GIBH-1006 >100 uM 56.06 nM 20.5 uM 79.5uM GIBH-1004 >100 uM >10 uM >100 uM 67.5 uM GIBH-1016 >100 uM 179.5nM >100 uM >100 uM GIBH-1008 >100 uM 61.75 nM 65.1 uM 78.5 uMGIBH-1010 >100 uM 67.10 nM 38.9 uM >100 uM GIBH-1012 >100 uM 54.46nM >100 uM >100 uM GIBH-1014 31.75 uM 36.84 nM >100 uM 45.22 uMGIBH-1018 >100 uM 63.74 nM >100 uM 78.90 uM GIBH-1051 5.446 uM 84.10 nM70.64 uM >100 uM

It can be seen from the enzyme activity test as shown in Table 1 that, aseries of compounds of the present invention have a nanomole level ofinhibition IC50 values onto the activity of human recombinant COX-2 andhas relatively poor inhibition onto the activity of COX-1. It isindicated that COX-2 has better section inhibition. For example, theIC50 value of the enzyme COX-2 of the compound CIBH1008 is 61.75nanomole, while the IC50 value of COX-1 is greater than 100 nanomole.Thus, a ratio of the selectivity of the compound CIBH1008 to COX-2 tothe selectivity of the compound CIBH1008 to COX-1 is greater than 1619,a ratio of the selectivity of the compound CIBH-1018 to COX-2 to theselectivity of the compound CIBH-1018 to COX-1 is greater than 1569, anda ratio of the selectivity of the compound CIBH-1014 to COX-2 to theselectivity of the compound CIBH-1014 to COX-1 is 862. The human wholeblood COX enzyme activity test also indicates that the compoundsGIBH1014 and GIBH1018 and the compound CIBH-1014 have better selectivityto the inhibition of COX-2 enzyme of blood cells.

Embodiment 23

Test on pharmacokinetics and bioavailability of rats: four male SD ratsper group, single-dose, oral administration 2.5-25 mg/kg, vein 1-5mg/kg, animal blood samples are collected at proper time points afterdrug administration, heparin anticoagulation, 3000 rpm*10 min, collectsupernatant, storage at −20° C. for LC/MS analysis. The blood samplesemploy acetonitrile to precipitate protein, 16000 rpm*30 min, and thesupernatant is used for LC/MS analysis. Data is performed with parameterfitting by DAS2.0, and the bioavailability of oral administration ofcompounds is calculated according AUC data. The results refer to thefollowing table.

TABLE 3 Pharmacokinetic study results of part of compounds Rat PK Thenumber Dose AUC Cmax t½ Tmax BA Vd of animals mg/kg ug/L*h ug/l h h %l/kg GIBH-1006 ♂4 25 511440.9 29525 9.54 1.625 78.6 0.68 GIBH-1004 ♂4 25180839.6 34150 2.88 0.563 46.1 0.58 GIBH-1016 ♂4 2.5 4325.4 4405 1.040.187 65.1 0.94 GIBH-1008 ♂4 10 118331.4 20900 2.1 1.167 92.8 0.26GIBH-1010 ♂4 10 84789.7 21399 3.35 0.5 111.8 0.57 GIBH-1012 ♂4 2.538881.9 8945 3.37 0.5 110.7 GIBH-1014 ♂4 10 142687 35300 5.2 0.417 107.40.53 GIBH-1018 ♂4 2.5 28340.5 11805 2.43 0.271 90.6 0.31 GIBH-1051 ♂42.5 13028.2 4485 1.759 0.688 63.7 1.004

AUC (Area Under the Curve): the area under the curve of concentration ofdrug in blood plasma against time, standing for the bioavailability ofdrug (the fraction of drug absorbed by human body). The larger the AUCis, the higher the bioavailability is; otherwise, the bioavailability islow. The AUC is called “area under concentration-time curve”. Forexample, the AUC value of GIBH-1006 is highest, so the bioavailabilityof GIBH-1006 is also maximal.

Cmax: the peak concentration refers to the maximum plasma-drugconcentration on the concentration-time curve, i.e., the maximum serumconcentration that a drug may achieve after the drug has beenadministrated. The peak concentration is closely related to clinicalapplications of a drug. The drug may have a conspicuous effect after theconcentration of the drug reaches the peak concentration, while the drugmay have a toxic response if the concentration of the drug is beyond asafe range. In addition, the peak concentration is also an importantindicator for the measurement of preparation absorption and safety.

T½ (half life time): is the time required for the drug plasmaconcentration to decrease by 50%, reflecting the speed of elimination bybiotransformation or excretion.

Tmax (Peak Time): time required for the curve of drug concentration inhuman plasma to reach the highest concentration (peak concentration).Short peak time indicates quick absorption and effect and shortresidence time; and long peak time indicates slow absorption and effectand long residence time. Tmax is an important index of drug applicationand preparation research.

BA (bioavailability): the speed and degree of absorption in the systemiccirculation. BA is further divided into absolute bioavailability andrelative bioavailability. The absolute bioavailability is a percentageof absorption of other forms and doses of this drug by organism whenthis drug is administrated intravenously and utilized 100%; and therelative bioavailability is a percentage of utilization of other formsof this drug when a certain form (for example, water preparation fororal administration) is unitized 100%.

Vd (apparent volume of distribution): a ratio of the amount of drugs inthe body to the drug plasma concentration when the drugs reach a dynamicbalance in the body. According to the plasma concentration (c), it isestimated a volume that the total amount (A) of administrated compoundswould have to occupy, that is, Vd=A/c (unit mL or mL/kg (body weight)).The smaller the Vd is, the quicker the excretion is and the shorter theresidence time is; instead, the larger the Vd is, the slower theexcretion is and the longer the residence time is. Vd is a theoreticalvolume, not a specifically physiological volume in the body. However, Vdmay reflect the degree of distribution of drugs or the degree of bindingwith macromolecules in the tissues.

The embodiments mentioned above are merely several implementations ofthe present invention. Although these embodiments have been describedspecifically and in details, these embodiments shall not be regarded asany limitation to the present patent. It should be noted that, thoseskilled in the art may make various variations and improvements withoutdeparting from the concept of the present invention, and thosevariations and improvements shall fall into the protection cope of thepresent invention. Therefore, the protection scope of the presentinvention is subject to the claims.

The invention claimed is:
 1. A method for inhibiting COX-2, the method comprising: contacting a COX-2 or a cell containing COX-2 with an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of O, S, and NR^(a), R^(a) is selected from the group consisting of H, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, C₁-C₃ alkyl substituted with one or two halo, and aryl; n is an integer selected from the group consisting of 1, 2, and 3; R is selected from the group consisting of carboxyl, acylamino, alkylsulfonyl, and alkoxycarbonyl; R₁ is selected from the group consisting of haloalkyl, alkyl, aralkyl, and cycloalkyl; R₂ is selected from the group consisting of deuterium, halogen, alkyl, deuteroalkyl, aralkyl, deuteroaralkyl, haloalkyl, deuterohaloalkyl, alkoxy, deuteroalkoxy, aryloxy, deuteroaryloxy, heteroaryloxy, deutero-heteroaryloxy, arylalkoxy, deutero-arylalkoxy, heteroarylalkoxy, deutero-heteroarylalkoxy, haloalkoxy, deutero-haloalkoxy, amino, deuteroamino, sulfamidyl, and deuterosulfamidyl; and R₃ is deuteroalkyl.
 2. The method of claim 1, wherein the cell is in a patient suffering from cancer.
 3. The method of claim 2, wherein the cancer is selected from the group consisting of hemangioma, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small-cell lung cancer, lung adenocarcinoma, squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, nasopharyngeal carcinoma, and leukemia.
 4. The method of claim 3, wherein the cancer is selected from the group consisting of non-small cell lung cancer, lung adenocarcinoma, and squamous cell carcinoma, pancreatic cancer.
 5. The method of claim 1, wherein the compound or salt is administered orally at a daily dose of 0.5-100 mg/day·kg.
 6. The method of claim 5, wherein the compound or salt is administered at a daily dose of 1-100 mg/day·kg.
 7. The method of claim 1, wherein the compound or salt is administered at a daily dose of 0.1 mg.
 8. The method of claim 1, wherein position 7 is unsubstituted; X is O or S; R is carboxyl, unsubstituted or aryl-substituted C₁-C₃ cyclocarbonyl, or C₁-C₃ alkoxycarbonyl; R₁ is haloalkyl; and each R₂ is independently selected from the group consisting of deuterium, halogen, alkyl, deuteroalkyl, haloalkyl, and deuterohaloalkyl.
 9. The method of claim 8, wherein n is selected from the group consisting of 1 and 2; R is selected from the group consisting of carboxyl, unsubstituted or aryl-substituted C₁-C₃ cyclocarbonyl, and C₁-C₃ alkoxycarbonyl; R₁ is selected from the group consisting of haloalkyl, cycloalkyl, and phenyl; and R₂ is selected from the group consisting of deuterium, halogen, alkyl, deuteroalkyl, haloalkyl, deuterohaloalkyl, alkoxy, deuteroalkoxy, alkylamino, deuteroalkylamino, alkylated sulfamidyl, and alkylated deuterosulfamidyl, wherein at least one R₂ is substituted at position 6 of the Formula (I) ring structure.
 10. The method of claim 1, wherein X is O, R is —COOH, R₁ is trifluoromethyl, and at least one R₂ is halo.
 11. The method of claim 1, wherein the compound is 8-(ethyl-D5)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, or a salt thereof.
 12. The method of claim 1, wherein the compound is 6-chloro-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, or a salt thereof.
 13. The method of claim 1, wherein the compound is 6-bromo-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, or a salt thereof.
 14. The method of claim 1, wherein the compound is 6,8-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, or a salt thereof.
 15. The method of claim 1, wherein the compound is 6-chloro-8-(1-methylhexyl-D15)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, or a salt thereof.
 16. The method of claim 1, wherein the compound is 7,8-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, or a salt thereof.
 17. The method of claim 1, wherein the compound is 6-chloro-8-(hexyl-D13)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, or a salt thereof.
 18. The method of claim 1, wherein the compound or salt is administered in a composition comprising at least one pharmaceutically acceptable carrier, excipient, or diluent. 